The scenario feels mostly the same as the basic game but there are of course some changes too. The pre-Columbian civilizations preferred taking prisoners instead of killing their opponents so that they could sacrifice them to the gods. In the scenario the opposing units may indeed be taken prisoners and then hauled to cities for sacrificing. There are two types of sacrifice rituals in the game: the Blood Ritual, which gives a culture bonus (), and the Sun Ritual, which gives a happiness bonus (). The size of the bonus depends the strength of the unit being sacrificed.

Diseases played a great role in the doom of the largest Native American civilizations. These diseases were brought to the Americas by the Europeans and killed the local populations which did not have any immunity against them. In the MesoAmerica scenario some Spanish units will periodically arrive to the player's shores, bringing smallpox with them. Units that are near other, infected units will also get infected themselves. Infected units slowly lose their strength but can also be used as biological weapons by having them infect enemy units or cities.